3-Benzyl-2H-1,3-benzoxazine-2,4(3H)-diones, a new group of antimycobacterial compounds against potentially pathogenic strains

Article abstract of DOI:10.1016/j.farmac.2003.07.004

A series of derivatives of 3-benzyl-2H-benzoxazine-2,4(3H)-dione substituted in positions 6, 7 or 8 on the benzoxazine, and in positions 3 or 4 on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. The disadvantage of the compounds is in their low solubility in water. The antimycobacterial activity of N-benzylsalicylamides correlates with that of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones and depends on the partition coefficients and electronic indexes.

Full text of DOI:10.1016/j.farmac.2003.07.004

Il Farmaco 58 (2003) 1137ꢀ1149
/
www.elsevier.com/locate/farmac
3-Benzyl-2H-1,3-benzoxazine-2,4(3H)-diones, a new group of
antimycobacterial compounds against potentially pathogenic strains
Karel Waisser a,*, Milan Perˇina a, Jirˇ´ı Kunesˇ a, Vera Klimesˇova´ a, Jarmila Kaustova´ b
a Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Hcyrovsky Str. 1203, Hradec Kra´love´ 50005,
Czech Republic
b Department for Diagnostics of Mycobacteria, Regional Institute of Public Health, Ostrava, Czech Republic
Received 16 May 2003; accepted 11 July 2003
Abstract
A series of derivatives of 3-benzyl-2H-benzoxazine-2,4(3H)-dione substituted in positions 6, 7 or 8 on the benzoxazine, and in
positions 3 or 4 on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against
Mycobacterium avium and two strains of Mycobacterium kansasii. The disadvantage of the compounds is in their low solubility in
water. The antimycobacterial activity of N-benzylsalicylamides correlates with that of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones
and depends on the partition coefficients and electronic indexes.
´
# 2003 Published by Editions scientifiques et me´dicales Elsevier SAS.
Keywords: Benzoxazines; Tuberculostatics; Antimycobacterial activity; Mycobacterium
1. Introduction
zine-2,4(3H)-diones are inhibitors of two-component
systems as well [4]. The goal of this work was to evaluate
structure-activity relationships in the series of 3-benzyl-
2H-benzoxazin-2,4(3H)-diones, substituted on the ben-
zyl moiety in positions 4 (or 3) and in positions 6, 7 or 8
on the benzoxazine, including a more detailed analysis
of the relationship.
The search for new antimycobacterial compounds is
one of the most challenging tasks of current medicinal
chemistry. Mycobacterial diseases due to multiresistant
strains are not frequent, but mostly fatal in the end. In
particular, the study of antimycobacterial properties of
salicylanilides is of great interest, as salicylanilides are
inhibitors of bacterial two-component systems [1,2] that
were also found in mycobacteria. Salicylanilides are
broad-spectrum antimycobacterial compounds. How-
ever, salicylanilides are unlikely to be effective che-
motherapeutic agents themselves due to their effect on
mitochondrial respiration [2]. Therefore, we are at-
tempting to find similar compounds not affecting
mitochondrial respiration. In our previous study, we
assumed that compounds isosteric to salicylanilides
would also display antimycobacterial activity [3]. Re-
cently, we have found that 3-benzyl-2H-1,3-benzoxa-
2. Chemistry
The synthetic pathway leading to 3-benzyl-2H-1,3-
benzoxazin-2,4(3H)-diones is depicted in Fig. 1. Sub-
stituted 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones
were prepared by the treatment of substituted N-
benzylsalicylamides with ethyl chloroformate in pyri-
1
dine. The structural assignment is based on H NMR
and 13C NMR spectra and IR spectra. In the IR spectra,
two absorption maxima of the carbonyl groups were
apparent. The synthesis of the starting N-benzylsalicy-
lamides has been reported [5]. An overview of the
compounds under study is in Fig. 2.
* Corresponding author.
E-mail address: waisser@faf.cuni.cz (K. Waisser).
´
0014-827X/03/$ - see front matter # 2003 Published by Editions scientifiques et me´dicales Elsevier SAS.
doi:10.1016/j.farmac.2003.07.004

1138
K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ1149
/
Fig. 1. Preparation of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones.
dry pyridine (20 ml) under ice-cooling. The mixture was
heated on a steam bath for 1 h and then poured into 5%
hydrochloric acid (140 ml). After 24 h, the product was
filtered off, suspended in 5% potassium hydroxide
solution, filtered off again, and crystallized from
EtOH (yield 39ꢀ70%).
/
3.1.1. 3-Benzyl-2H-1,3-benzoxazine-2,4(3H)-dione
(1a)
White crystals. Yield 45%, m.p. 173ꢀ
[6,7] 133ꢀ134 8C. IR (KBr): n(CÄ
O) 1701, 1757 cmꢁ1
log Pꢃ3.07. For C15H11NO3 (253.3) calc.: 71.14% C,
5.53% N, 4.38% H; found: 70.77% C, 5.46% N, 4.40%
/
175 8C, Refs.
/
/
,
/
1
Fig. 2. Overview of the structures of 3-benzyl-2H-1,3-benzoxazin-
2,4(3H)-diones.
H. H NMR (CDCl3) d 8.00 (dd, 1H, J(5,6)ꢃ
/
8.10 Hz,
J(5,7)ꢃ1.50 Hz, H5), 7.82ꢀ7.67 (m, 1H. H7), 7.46ꢀ
/
/
/7.26
(m, 7H, H6, H8, H2?, H3?, H4?, H5?, H6?), 5.06 (s, 2H,
CH2). 13C NMR (CDCl3) d 160.7, 152.6, 148.1, 136.6,
136.3, 128.6, 128.0, 127.9, 127.6, 125.6, 116.6, 114.3,
45.3.
3. Experimental
3.1. Chemistry
The melting points were determined on a Kofler
apparatus. The samples for analysis and antimycobac-
terial tests were dried over P4O10 at 61 8C and 66 Pa for
24 h. Elemental analyses (C, H, N) were performed on a
CHNS-O CE elemental analyzer (Fisons EA 1110,
3.1.2. 3-Benzyl-6-bromo-2H-1,3-benzoxazine-2,4(3H)-
dione (1b)
White crystals. Yield 52%, m.p. 158ꢀ
/
160 8C. IR
(KBr): n(CÄ
/
O) 1701, 1768 cmꢁ1, log Pꢃ
/
3.90. For
Milano) and were within90.4% of the theoretical
/
C15H10BrNO3 (332.2) calc.: 54.24% C, 4.22% N, 3.03%
H; found: 54.51% C, 4.22% N, 3.20% H. 1H NMR
values. The IR spectra were measured in KBr pellets
on a Nicolet Impact 400 apparatus; the wavenumbers
(CDCl3) d 8.19 (d, 1H, J(5,7)ꢃ
1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.40 Hz, H7), 7.52ꢀ
(m, 2H, H2?, H6?), 7.34ꢀ7.28 (m, 3H, H3?, H4?, H5?),
/
2.40 Hz, H5), 7.54 (dd,
are given in cmꢁ1. The bonding vibrations of the CÄ
/
O
/
/
/7.49
group [n(C
/
Á Á Á
/
O)] were found in the region 1686ꢀ
/
1707
/
cmꢁ1 and 1742ꢀ
2H-1,3-benzoxazine-2,4(3H)-diones. TLC was per-
/
1778 cmꢁ1, characteristic for 3-benzyl-
7.15 (d, 1H, J(7,8)ꢃ8.70 Hz, H8), 5.18 (s, 2H, CH2).
/
13C NMR (CDCl3) d 159.3, 151.4, 147.5, 139.0, 135.3,
130.6, 129.3, 129.2, 128.6, 128.2, 118.3, 118.2, 45.9.
formed on silica gel plates precoated with a fluorescent
indicator Silufol UV 254ꢂ
Republic), with heptaneꢀethylacetate (8:3) as the mobile
phase, or tolueneꢀ
acetone (10:1). The 1H NMR and 13
/366 (Kavalier, Votice Czech
/
/
C
3.1.3. 3-Benzyl-6-chloro-2H-1,3-benzoxazine-2,4(3H)-
dione (1c)
NMR spectra of new compounds were recorded in
DMSO-d6 or pyridine-d5 solution at ambient tempera-
ture on a Varian Mercury-Vx BB 300 spectrometer
operating at 300 MHz. Chemical shifts were recorded as
d values in parts per millions (ppm) and were indirectly
referenced to tetramethylsilane via the solvent signal
White crystals. Yield 62%, m.p. 144ꢀ
/
146 8C. IR
(KBr): n(CÄ
/
O) 1705, 1767 cmꢁ1, log Pꢃ
/
3.63. For
C15H10ClNO3 (287.7) calc.: 62.62% C, 4.87% N, 3.50%
H; found: 62.34% C, 4.76% N, 3.61% H. 1H NMR
1
(2.49 for H or 39.7 for 13C).
(DMSO-d6) d 7.94 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.70 Hz, H7), 7.49
(d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.52ꢀ7.49 (m, 5H, H2?,
/
2.70 Hz, H5), 7.88
The starting salicylanilides were described in our
previous paper [3]. The title compounds were synthe-
sized from the corresponding salicylamides. Ethyl chlor-
oformate (5.2 g, 48 mmol) was added dropwise to a
stirred solution of an N-benzylsalicylamide (40 mmol) in
/
/
/
/
H3?, H4?, H5?, H6?), 5.04 (s, 2H, CH2). 13C NMR
(DMSO-d6) d 159.9, 151.4, 147.8, 136.2, 136.1, 129.5,
128.6, 127.9, 127.7, 126.5, 118.9, 116.0, 45.5.

K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ
/1149
1139
3.1.4. 3-Benzyl-6,8-dichloro-2H-1,3-benzoxazine-
2,4(3H)-dione (1d)
(DMSO-d6) d 8.64 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ
(d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.41ꢀ
/
2.70 Hz, H5), 8.59
/
/2.70 Hz, H7), 7.70
White crystals. Yield 58%, m.p. 134ꢀ
/
136 8C. IR
/
/
7.29 (m, 5H, H2?,
(KBr): n(CÄ
/
O) 1701, 1772 cmꢁ1, log Pꢃ
/4.19. For
H3?, H4?, H5?, H6?), 5.07 (s, 2H, CH2). 13C NMR
(DMSO-d6) d 159.8, 156.4, 147.4, 144.4, 135.8, 130.9,
128.6, 128.0, 127.7, 123.1, 118.6, 115.5, 45.7.
C15H9Cl2NO3 (322.1) calc.: 55.93% C, 4.35% N, 2.82%
H; found: 56.28% C, 4.35% N, 3.01% H. 1H NMR
(DMSO-d6) d 8.19 (d, 1H, J(5,7)ꢃ/2.40 Hz, H5), 7.92
(d, 1H, J(5,7)ꢃ
/
2.40 Hz, H7), 7.40ꢀ
/
7.28 (m, 5H, H2?,
3.1.9. 3-Benzyl-7-chloro-2H-1,3-benzoxazine-2,4(3H)-
dione (1i)
H3?, H4?, H5?, H6?), 5.05 (s, 2H, CH2).13C NMR
(DMSO-d6) d 159.4, 147.8, 147.1, 135.8, 135.4, 129.4,
128.5, 127.9, 127.6, 125.6, 121.6, 117.4, 45.7.
White crystals. Yield 70%, m.p. 154ꢀ
/
155 8C. IR
(KBr): n(CÄ
/
O) 1688, 1754 cmꢁ1, log Pꢃ
/
3.63. For
C15H10ClNO3 (287.7) calc.: 62.62% C, 4.87% N, 3.50%
H; found: 62.34% C, 4.71% N, 3.48% H. 1H NMR
3.1.5. 3-Benzyl-6-methyl-2H-1,3-benzoxazine-2,4(3H)-
dione (1e)
(DMSO-d6) d (7.98 d, 1H, J(5,6)ꢃ
(d, 1H, J(6,8)ꢃ1.65 Hz, H8), 7.50 (dd, 1H, J(5,6)ꢃ
8.40 Hz, J(6,8)ꢃ1.65 Hz, H6), 7.38ꢀ7.28 (m, 5H, H2?,
/
8.40 Hz, H5), 7.69
White crystals. Yield 45%, m.p. 116ꢀ
/
120 8C. IR
/
/
(KBr): n(CÄ
/
O) 1689, 1757 cmꢁ1, log Pꢃ
/3.56. For
/
/
H3?, H4?, H5?, H6?), 5.04 (s, 2H, CH2). 13C NMR
(DMSO-d6) d 160.1, 153.1, 147.8, 140.6, 136.1, 129.2,
128.6, 127.9, 127.7, 125.9, 116.9, 113.6, 45.4.
C16H13NO3 (267.3) calc.: 71.90% C, 5.24% N, 4.90%
H; found: 71.84% C, 5.24% N, 4.86% H. 1H NMR
(DMSO-d6) d 7.78 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.10 Hz, J(5,7)ꢃ2.10 Hz, H7), 7.36ꢀ
/2.10 Hz, H5), 7.60
/
/
/
7.25 (m, 6H, H8, H2?, H3?, H4?, H5?, H6?), 5.05 (s, 2H,
CH2) 2.38 (s, 3H, CH3). 13C NMR (DMSO-d6) d 160.7,
150.7, 137.4, 136.4, 135.2, 128.6, 127.8, 127.6, 127.1,
116.4, 113.9, 45.2, 20.3.
3.1.10. 3-Benzyl-8-methoxy-2H-1,3-benzoxazine-
2,4(3H)-dione (1j)
White crystals. Yield 49%, m.p. 144ꢀ
/
146 8C. IR
(KBr): n(CÄ
/
O) 1697, 1756 cmꢁ1, log Pꢃ
/
2.95. For
C16H13NO4 (283.3) calc.: 67.84% C, 4.94% N, 4.63%
H; found: 67.89% C, 4.86% N, 4.30% H. 1H NMR
3.1.6. 3-Benzyl-6,8-dibromo-2H-1,3-benzoxazine-
2,4(3H)-dione (1f)
(DMSO-d6) d 7.51ꢀ
/
7.46 (m, 2H, H5, H7), 7.37ꢀ7.25 (m,
/
White crystals. Yield 65%, m.p. 169ꢀ
/
171 8C. IR
6H, H6, H2?, H3?, H4?, H5?, H6?), 5.10 (s, 2H, CH2),
3.80 (s, 3H, OCH3). 13C NMR (DMSO-d6) d 160.7,
147.9, 146.8, 142.2, 136.3, 128.6, 127.8, 127.6, 125.5,
118.3, 117.9, 115.1, 56.6, 45.3.
(KBr): n(CÄ
/
O) 1701, 1770 cmꢁ1, log Pꢃ
/4.73. For
C15H9Br2NO3 (411.0) calc.: 43.83% C, 3.41% N, 2.21%
H; found: 43.61% C, 3.21% N, 2.24% H. 1H NMR
(DMSO-d6) d 8.38 (d, 1H, J(5,7)ꢃ/2.70 Hz, H5), 8.06
(d, 1H, J(5,7)ꢃ
/
2.70 Hz, H7), 7.39ꢀ
/
7.26 (m, 5H, H2?,
H3?, H4?, H5?, H6?), 5.04 (s, 2H, CH2). 13C NMR
(DMSO-d6) d 159.4, 147.2, 140.8, 135.8, 128.1, 128.5,
127.5, 127.9, 127.7, 1176, 117.2, 110.8, 45.7.
3.1.11. 3-Benzyl-6-methoxy-2H-1,3-benzoxazine-
2,4(3H)-dione (1k)
White crystals. Yield 58%, m.p. 151ꢀ
/
152 8C. IR
(KBr): n(CÄ
/
O) 1687, 1754cmꢁ1, log Pꢃ
/2.95. For
C16H13NO4 (283.3) calc.: 67.84% C, 4.94% N, 4.63%
H; found: 67.95% C, 4.85% N, 4.52% H. 1H NMR
3.1.7. 3-Benzyl-7-methoxy-2H-1,3-benzoxazine-
2,4(3H)-dione (1g)
(CDCl3) d 7.40ꢀ7.25 (m, 8H, H5, H7, H8, H2?, H3?,
/
White crystals. Yield 46%, m.p. 134ꢀ
/
136 8C. IR
O) 1693, 1754 cmꢁ1, log Pꢃ
/2.95. For
H4?, H5?, H6?), 5.06 (s, 2H, CH2), 3.82 (s, 3H, OCH3).
13C NMR (CDCl3) d 160.7, 156.5, 148.1, 146.8, 136.3,
128.6, 127.9, 127.6, 124.4, 118.1, 114.7, 108.8, 56.1, 45.3.
(KBr): n(CÄ
/
C16H13NO4 (283.3) calc.: 67.84% C, 4.94% N, 4.63%
H; found: 67.90% C, 4.83% N, 4.69% H. 1H NMR
(DMSO-d6) d 7.88 (dd, 1H, J(5,6)ꢃ
0.90 Hz, H5), 7.37ꢀ7.25 (m, 5H, H2?, H3?, H4?, H5?,
H6?), 7.02ꢀ6.98 (m, 2H, H8, H6), 5.08 (s, 2H, CH2), 3.87
/
8.10 Hz, J(5,7)ꢃ
/
/
3.1.12. 3-(4-Chlorobenzyl)-2H-1,3-benzoxazine-
2,4(3H)-dione (2a)
/
(s, 3H, OCH3). 13C NMR (DMSO-d6) d 165.8, 160.2,
154.4, 148.3, 136.4, 129.1, 128.6, 127.8, 127.6, 113.6,
107.1, 100.5, 56.6, 45.0
White crystals. Yield 63%, m.p. 133-135 8C, Ref. [7]
127ꢀ
log Pꢃ
C, 4.87% N, 3.50% H; found: 62.54% C, 4.82% N, 3.55%
/
130 8C. IR (KBr): n(CÄ
/
O) 1693, 1760 cmꢁ1
,
/
3.63. For C15H10ClNO3 (287.7) calc.: 62.62%
1
3.1.8. 3-Benzyl-6-nitro-2H-1,3-benzoxazine-2,4(3H)-
dione (1h)
H. H NMR (DMSO-d6) d 7.98 (dd, 1H, J(5,6)ꢃ
/
8.10
Hz, J(5,7)ꢃ2.10 Hz, H5), 7.84ꢀ7.79 (m, 1H, H6), 7.46ꢀ
/
/
/
Yellow crystals. Yield 65%, m.p. 164ꢀ
/
165 8C. IR
7.35 (m, 6H, H7, H8, H2?, H3?, H5?, H6?), 5.03 (s, 2H,
CH2). 13C NMR (DMSO-d6) d 160.7, 152.6, 148.1,
136.6, 135.3, 132.2, 129.9, 128.5, 127.6, 125.6, 116.6,
114.4, 44.7.
(KBr): n(CÄ
/
O) 1705, 1774 cmꢁ1, log Pꢃ
/2.46. For
C15H10N2O5 (298.3) calc.: 60.41% C, 9.39% N, 3.38%
H; found: 60.67% C, 9.23% N, 3.47% H. 1H NMR

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K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ1149
/
3.1.13. 6-Bromo-3-(4-chlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (2b)
1.81% H; found: 40.06% C, 3.15% N, 1.81% H. 1H
NMR (CDCl3) d 8.38 (d, 1H, J(5,7)ꢃ2.40 Hz, H5),
8.05 (d, 1H, J(5,7)ꢃ2.40 Hz, H7), 7.42ꢀ7.38 (m
AA?BB?, 4H, H2?, H3?, H5?, H6?), 5.02 (s, 2H, CH2).
13C NMR (CDCl3) d 159.4, 149.6, 147.2, 140.8, 134.8,
132.3, 129.9, 129.0, 128.5, 117.7, 117.2, 110.8, 45.1.
/
White crystals. Yield 52%, m.p. 206ꢀ
/
208 8C. IR
/
/
(KBr): n(CÄ
/
O) 1694, 1759 cmꢁ1, log Pꢃ
/4.46. For
C15H9BrClNO3 (366.6) calc.: 49.14% C, 3.82% N,
2.43% H; found: 49.19% C, 3.80% N, 2.43% H. 1H
NMR (CDCl3) d 8.06 (d, 1H, J(5,7)ꢃ
7.98 dd, 1H, J(7,8)ꢃ9.00 Hz, J(5,7)ꢃ
7.44 d, 1H, J(7,8)ꢃ9.00 Hz, H8), 7.42ꢀ
/
2.40 Hz, H5),
2.40 Hz, H7),
7.35 (m
/
/
3.1.18. 3-(4-Chlorobenzyl)-7-methoxy-2H-1,3-
benzoxazine-2,4(3H)-dione (2g)
/
/
AA?BB?, 4H, H2?, H3?, H5?, H6?), 5.02 (s, 2H, CH2).
13C NMR (CDCl3) d 159.8, 151.8, 147.7, 139.0, 135.1,
132.2, 129.9, 129.4, 128.5, 119.2, 117.1, 116.5, 44.9.
White crystals. Yield 56%, m.p. 154ꢀ
/
156 8C. IR
(KBr): n(CÄ
/
O) 1698, 1778 cmꢁ1, log Pꢃ
/
3.50. For
C16H12ClNO4 (317.7) calc.: 60.48% C, 4.41% N, 3.81%
H; found: 60.80% C, 4.48% N, 3.85% H. 1H NMR
3.1.14. 6-Chloro-3-(4-chlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (2c)
(DMSO-d6) d 7.88 (dd, 1H, J(5,6)ꢃ
0.90 Hz, H5), 7.41ꢀ7.35 (m, 4H, H6, H8, H2?, H6?),
7.00ꢀ
/
9.30 Hz, J(5,8)ꢃ
/
/
White crystals. Yield 49%, m.p. 198ꢀ
/
199 8C. IR
/
6.98 (m AA?BB?, 2H, H3?, H5?), 5.01 (s, 2H, CH2),
O) 1697, 1765 cmꢁ1, log Pꢃ
/4.19. For
3.87 (s, 3H, OCH3). 13C NMR (DMSO-d6) d 165.8,
160.2, 154.5, 148.3, 135.5, 132.2, 129.9, 129.0, 128.5,
113.5, 107.1, 100.5, 56.6, 44.5.
(KBr): n(CÄ
/
C15H9Cl2NO3 (322.1) calc.: 55.93% C, 4.35% N, 2.82%
H; found: 55.58% C, 4.30% N, 2.77% H. 1H NMR
(DMSO-d6) d 7.94 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.40 Hz, H7), 7.51
(d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.42ꢀ7.35 (m AA?BB?,
/2.40 Hz, H5), 7.88
/
/
3.1.19. 3-(4-Chlorobenzyl)-6-nitro-2H-1,3-benzoxazine-
2,4(3H)-dione (2h)
/
/
4H, H2?, H3?, H5?, H6?), 5.02 (s, 2H, CH2). 13C NMR
(DMSO-d6) d 159.9, 151.4, 147.8, 136.2, 135.1, 132.3,
129.9, 129.5, 128.5, 126.5, 119.0, 116.1, 44.9.
Yellow crystals. Yield 67%, m.p. 186ꢀ
/
188 8C. IR
(KBr): n(CÄ
/
O) 1701, 1771 cmꢁ1, log Pꢃ
/
3.08. For
C15H9ClN2O5 (332.7) calc.: 54.15% C, 8.42% N, 2.73%
H; found: 54.26% C, 8.53% N, 2.72% H. 1H NMR
3.1.15. 6,8-Dichloro-3-(4-chlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (2d)
(DMSO-d6) d 8.62 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.40 Hz, H7), 7.72
(d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.40ꢀ7.37 (m AA?BB?,
/
2.40 Hz, H5), 8.59
/
/
White crystals. Yield 68%, m.p. 200ꢀ
/
202 8C. IR
/
/
(KBr): n(CÄ
/
O) 1691, 1772cmꢁ1, log Pꢃ
/
4.75. For
4H, H2?, H3?, H5?, H6?), 5.05 (s, 2H, CH2). 13C NMR
(DMSO-d6) d 159.8, 156.3, 147.4, 144.3, 134.8, 132.4,
130.9, 130.0, 128.5, 123.0, 118.6, 115.5, 45.1.
C15H8Cl3NO3 (356.6) calc.: 50.52% C, 3.93% N, 2.26%
H; found: 50.78% C, 3.83% N, 2.25% H. 1H NMR
(DMSO-d6) d 8.18 (d, 1H, J(5,7)ꢃ/2.70 Hz, H5), 7.91
(d, 1H, J(5,7)ꢃ
/
2.70 Hz, H7), 7.42ꢀ
/
7.35 (m AA?BB?,
4H, H2?, H3?, H5?, H6?), 5.01 (s, 2H, CH2). 13C NMR
(DMSO-d6) d 159.5, 147.8, 147.1, 135.5, 134.8, 132.3,
129.9, 129.4, 128.4, 125.5, 121.6, 117.5, 45.2.
3.1.20. 7-Chloro-3-(4-chlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (2i)
White crystals. Yield 49%, m.p. 174ꢀ
/
175 8C. IR
(KBr): n(CÄ
/
O) 1686, 1752 cmꢁ1, log Pꢃ
/
4.19. For
C15H9Cl2NO3 (322.1) calc.: 55.93% C, 4.35% N, 2.82%
H; found: 56.32% C, 4.44% N, 2.80% H. 1H NMR
3.1.16. 3-(4-Chlorobenzyl)-6-methyl-2H-1,3-
benzoxazine-2,4(3H)-dione (2e)
(DMSO-d6) d 7.98 (d, 1H, J(5,6)ꢃ
(d, 1H, J(6,8)ꢃ2.40 Hz, H8), 7.50 (dd, 1H, J(5,6)ꢃ
8.40 Hz, J(5,6)ꢃ2.40 Hz, H6), 7.42ꢀ7.36 (m AA?BB?,
/
8.40 Hz, H5), 7.70
White crystals. Yield 71%, m.p. 186ꢀ
/
188 8C. IR
O) 1693, 1757cmꢁ1, log Pꢃ
/
4.12. For
/
/
(KBr): n(CÄ
/
/
/
C16H12ClNO3 (301.7) calc.: 63.69% C, 4.64% N, 4.01%
H; found: 63.64% C, 4.31% N, 3.90% H. 1H NMR
4H, H2?, H3?, H5?, H6?), 5.02 (s, 2H, CH2). 13C NMR
(DMSO-d6) d 160.2, 153.2, 147.8, 140.6, 135.1, 132.3,
129.9, 129.2, 128.5, 125.9, 116.8, 113.6, 44.8.
(DMSO-d6) d 7.77 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.10 Hz, J(5,7)ꢃ2.10 Hz, H7), 7.33ꢀ
/2.10 Hz, H5), 7.63
/
/
/
7.15 (m 5H, H8, H2?, H3?, H5?, H6?), 5.03 (s, 2H, CH2),
2.38 (s, 3H, CH3). 13C NMR (DMSO-d6) d 160.8, 150.7,
148.2, 137.3, 135.4, 135.1, 132.2, 129.8, 128.5, 127.1,
116.4, 114.0, 44.7, 20.3.
3.1.21. 3-(4-Chlorobenzyl)-8-methoxy-2H-1,3-
benzoxazine-2,4(3H)-dione (2j)
White crystals. Yield 68%, m.p. 172ꢀ
/
174 8C. IR
(KBr): n(CÄ
/
O) 1687, 1754 cmꢁ1, log P ꢃ
/3.50. For
3.1.17. 6,8-Dibromo-3-(4-chlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (2f)
C16H12ClNO4 (317.7) calc.: 60.48% C, 4.41% N, 3.81%
H; found: 60.35% C, 4.25% N, 3.89% H. 1H NMR
White crystals. Yield 41%, m.p. 245ꢀ
(KBr): n(CÄ
O) 1693, 1752 cmꢁ1, log Pꢃ
C15H8Br2ClNO3 (445.5) calc.: 40.44% C, 3.14% N,
/
247 8C. IR
(DMSO-d6) d 7.51ꢀ
/
7.47 (m, 2H, H5, H7), 7.41ꢀ7.32 (m,
/
/
/5.29. For
5H, H6, H2?, H3?, H5?, H6?), 5.02 (s, 2H, CH2), 3.91 (s,
3H, OCH3). 13C NMR (DMSO-d6) d 160.8, 147.9,

K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ
/1149
1141
146.8, 142.3, 135.3, 132.2, 129.8, 128.5, 125.5, 118.3,
117.9, 115.2, 56.6, 44.7.
3.1.26. 6,8-Dichloro-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3d)
White crystals. Yield 58%, m.p. 171ꢀ
/
173 8C. IR
3.1.22. 3-(4-Chlorobenzyl)-6-methoxy 2H-1,3-
benzoxazine-2,4(3H)-dione (2k)
(KBr): n(CÄ
/
O) 1693, 1757cmꢁ1, log Pꢃ
/4.68. For
C16H11Cl2NO3 (336.2) calc.: 57.17% C, 4.17% N,
3.30% H; found: 57.38% C, 4.13% N, 2.92% H. 1H
White crystals. Yield 54%, m.p. 192ꢀ
/
194 8C. IR
(KBr): n(CÄ
/
O) 1691, 1757 cmꢁ1, log Pꢃ
/3.50. For
NMR (DMSO-d6) d 8.18 (d, 1H, J(5,7)ꢃ/2.40 Hz, H5),
C16H12ClNO4 (317.7) calc.: 60.48% C, 4.41% N, 3.81%
H; found: 60.52% C, 4.45% N, 4.00% H. 1H NMR
7.91 (d, 1H, J(5,7)ꢃ2.40 Hz, H7), 7.28ꢀ
/
/7.10 (m
AA?BB?, 4H, H2, H3?, H5?, H6?), 5.00 (s, 2H, CH2),
2.25 (s, 3H, CH3). 13C NMR (DMSO-d6) d 159.4, 147.6,
?
(DMSO-d6) d 7.78 (d, 1H, J(5,7)ꢃ/3.00 Hz, H5), 7.62
(dd, 1H, J(7,8)ꢃ9.00 Hz, J(5,7)ꢃ3.00 Hz, H7), 7.42ꢀ
/
/
/
147.0, 136.9, 135.4, 132.8, 129.3, 129.1, 128.0, 125.6,
121.6, 117.4, 45.5, 20.9.
7.32 (m, 5H, H8, H2?, H3?, H5?, H6?), 4.51 (s, 2H, CH2),
3.82 (s, 3H, OCH3). 13C NMR (DMSO-d6) d 160.8,
156.5, 150.7, 148.2, 137.4, 135.4, 135.2, 132.2, 129.8,
128.5, 118.1, 116.4, 56.8, 44.7.
3.1.27. 6-Methyl-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3e)
3.1.23. 3-(4-Methylbenzyl)-2H-1,3-benzoxazine-
2,4(3H)-dione (3a)
White crystals. Yield 47%, m.p. 145ꢀ
/
147 8C. IR
(KBr): n(CÄ
/
O) 1693, 1772 cmꢁ1, log Pꢃ
/
4.05. For
White crystals. Yield 68%, m.p. 132ꢀ
134ꢀ1368C. IR (KBr): n(CÄ
O) 1701, 1752 cmꢁ1
log Pꢃ3.56. For C16H13NO3 (267.3) calc.: 71.90% C,
5.24% N, 4.90% H; found: 71.61% C, 5.18% N, 5.00%
H. 1H NMR (DMSO-d6) d 8.00ꢀ
7.96 (m, 1H, H5),
7.81ꢀ7.78 (m, 1H, H7), 7.46ꢀ7.41 (m, 2H, H6, H8),
7.26ꢀ
/
133 8C, Ref. [7]
C17H15NO3 (281.3) calc.: 72.58% C, 4.98% N, 5.37%
H; found: 72.65% C, 5.02% N, 5.61% H. 1H NMR
/
/
,
/
(DMSO-d6) d 7.77 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.40 Hz, H7), 7.31
(d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.25ꢀ7.17 (m AA?BB?,
2H, H2?, H6?), 7.13ꢀ7.09 (m AA?BB?, 2H, H3?, H5?),
/
2.40 Hz, H5), 7.62
/
/
/
/
/
/
/
/
?
?
/
7.10 (m AA?BB?, 4H, H2?, H3?, H5?, H6?), 5.01 (s,
5.00 (s, 2H, CH2), 2.38 (s, 3H, CH3), 2.25 (s, 3H, CH3).
13C NMR (DMSO-d6) d 160.7, 150.6, 148.1, 137.3,
136.8, 135.2, 133.4, 129.1, 127.9, 127.1, 116.4, 113.9,
44.9, 20.8, 20.3.
2H, CH2), 2.25 (s, 3H, CH3). 13C NMR (DMSO-d6) d
160.7, 152.6, 149.0, 136.8, 136.6, 133.3, 129.1, 127.8,
127.6, 125.6, 116.6, 114.3, 45.0, 20.9.
?
3.1.24. 6-Bromo-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3b)
3.1.28. 6,8-Dibromo-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3f)
White crystals. Yield 62%, m.p. 195ꢀ
/
197 8C. IR
(KBr): n(CÄ
/
O) 1697, 1765 cmꢁ1, log Pꢃ
/4.39. For
White crystals. Yield 65%, m.p. 217ꢀ
/
219 8C. IR
C16H12BrNO3 (346.2) calc.: 55.51% C, 4.05% N, 3.49%
H; found: 55.78% C, 3.95% N, 3.42% H. 1H NMR
(KBr): n(CÄ
/
O) 1691, 1759 cmꢁ1, log P ꢃ
/5.22. For
C16H11Br2NO3 (425.1) calc.: 45.21% C, 3.30% N, 2.61%
H; found: 45.51% C, 3.28% N, 2.31% H. 1H NMR
(DMSO-d6) d 8.06 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ9.00 Hz, J(5,7)ꢃ2.40 Hz, H7), 7.44
(d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.26ꢀ7.23 (m AA?BB?,
2H, H2?, H6?), 7.13ꢀ
/2.40 Hz, H5), 7.97
/
/
(CDCl3) d 8.38 (d, 1H, J(5,7)ꢃ
/
2.40 Hz, H5), 8.04 (d,
7.10 (m AA?BB?, 4H,
/
/
1H, J(5,7)ꢃ2.40 Hz, H7), 7.27ꢀ
/
/
/
7.09 (m AA?BB?, 2H, H3?, H5?),
H2?, H3?, H5?, H6?), 4.99 (s, 2H, CH2), 2.26 (s, 3H,
4.99 (s, 2H, CH2), 2.25 (s, 3H, CH3). 13C NMR (DMSO-
d6) d 159.7, 151.8, 147.7, 138.9, 136.9, 133.1, 129.5,
129.1, 128.0, 126.5, 119.2, 116.4, 45.3, 20.9.
CH3). 13C NMR (CDCl3) d 159.3, 149.2, 147.1, 140.8,
?
?
136.9, 132.8, 129.1, 129.0, 128.0, 117.6, 117.2, 110.9,
45.5, 20.9.
3.1.25. 6-Chloro-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3c)
3.1.29. 7-Methoxy-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3g)
White crystals. Yield 53%, m.p. 171ꢀ
/
172 8C. IR
(KBr): n(CÄ
/
O) 1690, 1781 cmꢁ1, log Pꢃ
/4.12. For
White crystals. Yield 45%, m.p. 126ꢀ
/
128 8C. IR
C16H12ClNO3 (301.7) calc.: 63.69% C, 4.64% N, 4.01%
H; found: 63.80% C, 4.38% N, 4.15% H. 1H NMR
(KBr): n(CÄ
/
O) 1700, 1773 cmꢁ1, log Pꢃ
/
3.43. For
C17H15NO4 (297.3) calc.: 68.68% C, 4.71% N, 5.26%
H; found: 68.80% C, 4.56% N, 5.26% H. 1H NMR
(DMSO-d6) d 7.94 (d, 1H J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ
(d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.27ꢀ
2H, H2?, H6?), 7.13ꢀ
/
2.40 Hz, H5), 7.86
2.40 Hz, H7), 7.51
7.23 (m AA?BB?,
/
/
(DMSO-d6) d 7.87 (dd, 1H, J(5,6)ꢃ
/
9.00 Hz, J(5,8)ꢃ
/
/
/
0.60 Hz, H5), 7.13ꢀ7.08 (m AA?BB?, 4H, H2?, H3?, H5?,
/
/
7.09 (m AA?BB?, 2H, H3?, H5?),
H6?), 7.01ꢀ
/
6.96 (m, 2H, H6, H8), 4.97 (s, 2H, CH2), 3.87
4.99 (s, 2H, CH2), 2.25 (s, 3H, CH3). 13C NMR (DMSO-
d6) d 159.8, 151.4, 147.7, 136.9, 136.1, 133.1, 129.5,
129.1, 128.0, 126.5, 118.9, 116.1, 45.3, 20.9.
(s, 3H, OCH3), 2.24 (s, 3H, CH3). 13C NMR (DMSO-d6)
d 160.7, 152.6, 149.0, 136.8, 136.6, 133.3, 129.1, 127.8,
127.6, 125.6, 116.6, 114.3, 56.6, 45.0, 20.9.
?
?

1142
K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ1149
/
3.1.30. 3-(4-Methylbenzyl)-6-nitro-2H-1,3-benzoxazine-
2,4(3H)-dione (3h)
3.1.34. 3-(4-Fluorobenzyl)-2H-1,3-benzoxazine-
2,4(3H)-dione (4a)
Yellow crystals. Yield 68%, m.p. 168ꢀ
/
170 8C. IR
White crystals. Yield 45%, m.p. 152ꢀ
138ꢀ141 8C. IR (KBr): n(CÄ
O) 1698, 1755 cmꢁ1
log Pꢃ3.23. For C15H10FNO3 (271.2) calc.: 66.42% C,
5.16% N, 3.72% H; found: 66.36% C, 5.17% N, 3.58%
/
153 8C, Ref. [7]
(KBr): n(CÄ
/
O) 1692, 1771 cmꢁ1, log Pꢃ
/2.88. For
/
/
,
C16H12N2O5 (312.3) calc.: 61.54% C, 8.97% N, 3.87%
H; found: 61.51% C, 8.62% N, 3.88% H. 1H NMR
/
1
(DMSO-d6) d 8.62 (dd, 1H, J(7,8)ꢃ
3.00 Hz, H7), 8.58 (d, 1H, J(5,7)ꢃ3.00 Hz, H5), 7.70 (d,
1H, J(7,8)ꢃ8.40 Hz, H8), 7.21ꢀ7.14 (m AA?BB?, 4H,
/
8.40 Hz, J(5,7)ꢃ
/
H. H NMR (DMSO-d6) d 8.00 (d, 1H, J(5,6)ꢃ
Hz, H5), 7.80ꢀ7.73 (m, 1H, H7), 7.46ꢀ7.40 (m AA?BB?,
4H, H2?, H3?, H5?, H6?), 7.16ꢀ7.10 (m, 2H, H6, H8),
5.03 (s, 2H, CH2). 13C NMR (DMSO-d6) d 163.3, 160.4
(d, Jꢃ197.1 Hz), 152.6, 148.1, 136.6, 132.5 (d, Jꢃ11.4
Hz), 130.2 (d, Jꢃ33.0 Hz), 127.5, 125.6, 116.6, 115.3 (d,
Jꢃ85.2 Hz), 114.4, 44.6.
/1.80
/
/
/
/
/
/
H2?, H3?, H5?, H6?), 5.02 (s, 2H, CH2), 2.26 (s, 3H,
CH3). 13C NMR (DMSO-d6) d 159.7, 156.3, 147.3,
/
/
?
144.3, 136.9, 132.8, 130.9, 129.0, 128.1, 123.1, 118.6,
115.4, 45.5, 20.9.
/
/
3.1.35. 6-Bromo-3-(4-fluorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (4b)
3.1.31. 7-Chloro-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3i)
White crystals. Yield 58%, m.p. 176ꢀ
/
179 8C. IR
(KBr): n(CÄ
/
O) 1698, 1764 cmꢁ1, log Pꢃ
/
4.06. For
White crystals. Yield 47%, m.p. 163ꢀ
/
164 8C. IR
(KBr): n(CÄ
/
O) 1694, 1742 cmꢁ1, log Pꢃ
/
4.12. For
C15H9BrFNO3 (350.1) calc.: 51.45% C, 4.00% N,
2.59% H; found: 51.21% C, 3.89% N, 2.67% H. 1H
C16H12ClNO3 (301.7) calc.: 63.69% C, 4.64% N, 4.01%
H; found: 63.71% C, 4.56% N, 3.76% H. 1H NMR
NMR (DMSO-d6) d 8.06 (d, 1H, J(5,7)ꢃ
7.98 (dd, 1H, J(5,7)ꢃ8.70 Hz, J(5,7)ꢃ2.40 Hz, H7),
7.45ꢀ7.40 (m, 3H, H8, H2?, H6?), 7.16ꢀ7.11 (m AA?BB?,
2H, H3?, H5?), 5.02 (s, 2H, CH2). 13C NMR (DMSO-d6)
d 163.3, 150.8 (d, Jꢃ195.2 Hz), 151.8, 147.8, 138.9,
132.3 (d, Jꢃ11.4 Hz), 130.3 (d, Jꢃ31.4 Hz), 129.4,
119.2, 117.1, 116.5, 115.3 (d, Jꢃ85.5 Hz), 44.8.
/2.40 Hz, H5),
/
/
(DMSO-d6) d 7.98 (d, 1H, J(5,6)ꢃ
(d, 1H, J(6,8)ꢃ2.10 Hz, H8), 7.50 (dd, 1H, J(5,6)ꢃ
8.10 Hz, J(6,8)ꢃ2.10 Hz, H6), 7.26ꢀ7.01 (m AA?BB?,
/8.10 Hz, H5), 7.69
/
/
/
/
/
/
/
4H, H2?, H3?, H5?, H6?), 4.99 (s, 2H, CH2), 2.25 (s, 3H,
CH3). 13C NMR (DMSO-d6) d 160.1, 153.1, 147.8,
/
/
?
/
140.5, 136.9, 133.1, 129.1, 129.1, 128.0, 125.9, 116.8,
113.5, 45.1, 20.9.
3.1.36. 6-Chloro-3-(4-fluorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (4c)
White crystals. Yield 65%, m.p. 163ꢀ
/
165 8C. IR
O) 1764, 1701 cmꢁ1, log Pꢃ
/
3.79. For
3.1.32. 8-Methoxy-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3j)
(KBr): n(CÄ
/
C15H9ClFNO3 (305.7) calc.: 58.94% C, 4.58% N,
2.97% H; found: 59.29% C, 4.52% N, 2.97% H. 1H
Yield 62%, m.p. 132ꢀ
1755 cmꢁ1, log Pꢃ
3.43. For C17H15NO4 (297.3) calc.:
68.68% C, 4.71% N, 5.26% H; found: 68.58% C, 4.77%
N, 5.04% H. 1H NMR (DMSO-d6) d 7.52ꢀ
7.46 (m, 2H,
H5, H7), 7.35 (t, 1H, J(5,6)ꢃ7.80 Hz, H6), 7.25ꢀ7.10
/
133 8C. IR (KBr): n(CÄ
/
O) 1694,
/
NMR (DMSO-d6) d 7.94 (d, 1H, J(5,7)ꢃ
7.86 (dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.40 Hz, H7), d
7.49 (d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.46ꢀ7.41 (m
AA?BB?, 2H, H2?, H6?), 7.17ꢀ7.11 (m AA?BB?, 2H,
H3?, H5?), 5.02 (s, 2H, CH2). 13C NMR (DMSO-d6) d
161.8, 160.0 (d, Jꢃ190.2 Hz), 151.4, 147.8, 136.2, 132.3
(d, Jꢃ12.3 Hz), 130.3 (d, Jꢃ33.0 Hz), 129.5, 126.5,
118.9, 116.1, 115.3 (d, Jꢃ85.5 Hz), 44.9.
/2.40 Hz, H5),
/
/
/
/
/
/
/
/
(m AA?BB?, 4H, H2?, H3?, H5?, H6?), 5.00 (s, 2H, CH2),
3.90 (s, 3H, OCH3), 2.25 (s, 3H, CH3). 13C NMR
?
/
(DMSO-d6) d 160.7, 147.8, 146.8, 142.2, 136.8, 133.3,
129.1, 127.9, 125.5, 118.3, 117.9, 115.1, 56.6, 45.0, 20.9.
/
/
/
3.1.37. 6,8-Dichloro-3-(4-fluorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (4d)
3.1.33. 6-Methoxy-3-(4-methylbenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (3k)
White crystals. Yield 43%, m.p. 160ꢀ
/
161 8C. IR
White crystals. Yield 56%, m.p. 163ꢀ
/
165 8C. IR
(KBr): n(CÄ
/
O) 1700, 1770 cmꢁ1, log Pꢃ
/
4.35. For
(KBr): n(CÄ
/
O) 1686, 1750 cmꢁ1, log Pꢃ
/3.43. For
C15H8Cl2FNO3 (340.1) calc.: 52.97% C, 4.12% N,
2.37% H; found: 52.66% C, 3.96% N, 2.32% H. 1H
C17H15NO4 (297.3) calc.: 68.68% C, 4.71% N, 5.26%
H; found: 68.45% C, 4.87% N, 5.15% H. 1H NMR
NMR (DMSO-d6) d 8.19 (d, 1H, J(5,7)ꢃ
7.91 (d, 1H, J(5,7)ꢃ2.40 Hz, H7), 7.47ꢀ
AA?BB?, 2H, H2?, H6?), 7.17ꢀ7.11 (m AA?BB?, 2H,
H3?, H5?), 5.02 (s, 2H, CH2). 13C NMR (DMSO-d6) d
163.4, 159.8 (d, Jꢃ212.7 Hz), 147.8, 147.1, 135.4, 132.0
(d, Jꢃ11.4 Hz), 130.3 (d, Jꢃ33.0 Hz), 129.3, 125.6,
121.6, 117.4, 115.3 (d, Jꢃ85.2 Hz), 45.1.
/2.40 Hz, H5),
(DMSO-d6) d 7.40ꢀ
/
7.30 (m, 3H, H5, H7, H8), 7.25ꢀ
/
/
/7.41 (m
7.22 (m AA?BB?, 2H, H2?, H6?), 7.13ꢀ
/
7.09 (m AA?BB?,
/
2H, H3?, H5?), 5.00 (s, 2H, CH2), 3.82 (s, 3H, OCH3),
2.24 (s, 3H, CH3). 13C NMR (DMSO-d6) d 160.6, 156.5,
/
?
148.1, 146.8, 136.8, 133.4, 129.1, 127.9, 124.3, 118.1,
114.7, 108.8, 56.1, 45.1, 20.9.
/
/
/

K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ
/1149
1143
3.1.38. 3-(4-Fluorobenzyl)-6-methyl-2H-1,3-
benzoxazine-2,4(3H)-dione (4e)
130.9, 130.4 (d, Jꢃ
/
32.1 Hz), 123.0, 118.6, 115.5, 115.3
(d, Jꢃ85.5 Hz), 45.1.
/
White crystals. Yield 57%, m.p. 167ꢀ
/
169 8C. IR
(KBr): n(CÄ
/
O) 1695, 1757 cmꢁ1, log Pꢃ
/3.72. For
3.1.42. 7-Chloro-3-(4-fluorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (4i)
C16H12FNO3 (285.3) calc.: 67.36% C, 4.91% N, 4.24%
H; found: 67.64% C, 4.77% N, 4.45% H. 1H NMR
White crystals. Yield 58%, m.p. 144ꢀ
/
146 8C. IR
O) 1756, 1693 cmꢁ1, log Pꢃ
/
3.79. For
(DMSO-d6) d 7.74 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.40 Hz, H7), 7.43ꢀ
7.39 (m AA?BB?, 2H, H2?, H6?), 7.33 (d, 1H, J(7,8)ꢃ
8.70 Hz, H8), 7.18ꢀ7.12 (m AA?BB?, 2H, H3?, H5?), 5.02
(s, 2H, CH2), 2.38 (s, 3H, CH3). 13C NMR (DMSO-d6)
d 163.3, 160.7 (d, Jꢃ210.5 Hz), 150.7, 148.2, 137.3,
135.2, 132.6 (d, Jꢃ12.6 Hz), 130.2 (d, Jꢃ33.0 Hz),
127.0, 116.4, 115.3 (d, Jꢃ85.5 Hz), 113.9, 44.6.
/
2.40 Hz, H5), 7.60
(KBr): n(CÄ
/
/
/
/
C15H9ClFNO3 (305.7) calc.: 58.94% C, 4.58% N,
2.97% H; found: 58.64% C, 4.46% N, 2.87% H. 1H
/
/
NMR (DMSO-d6) d 7.98 (d, 1H, J(5,6)ꢃ
7.69 (d, 1H, J(6,8)ꢃ1.80 Hz, H8), 7.50 (dd, 1H,
J(5,6)ꢃ8.40 Hz, J(6,8)ꢃ1.80 Hz, H6), 7.45ꢀ7.41 (m
AA?BB?, 2H, H2?, H6?), 7.17ꢀ7.10 (m AA?BB?, 2H, H3?,
H5?), 5.02 (s, 2H, CH2). 13C NMR (DMSO-d6) d 161.8
(d, Jꢃ238.4 Hz), 160.1, 153.1, 147.8, 140.5, 132.3 (d,
Jꢃ12.6 Hz), 130.3 (d, Jꢃ33.0 Hz), 129.1, 125.9, 116.8,
115.3 (d, Jꢃ84.3 Hz), 113.6, 44.8.
/8.40 Hz, H5),
/
/
/
/
/
/
/
/
/
/
/
/
3.1.39. 6,8-Dibromo-3-(4-fluorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (4f)
/
White crystals. Yield 49%, m.p. 196ꢀ
/
197 8C. IR
(KBr): n(CÄ
/
O) 1697, 1772 cmꢁ1, log Pꢃ
/4.89. For
3.1.43. 3-(4-Fluorobenzyl)-8-methoxy-2H-1,3-
benzoxazine-2,4(3H)-dione (4j)
C15H8Br2FNO3 (429.0) calc.: 41.99% C, 3.26% N,
1.88% H; found: 41.98% C, 3.19% N, 1.92% H. 1H
White crystals. Yield 56%, m.p. 179ꢀ
/
181 8C. IR
O) 1688, 1755 cmꢁ1, log Pꢃ
/
3.10. For
NMR (DMSO-d6) d 8.37 (d, 1H, J(5,7)ꢃ
8.05 (d, 1H, J(5,7)ꢃ2.40 Hz, H7), 7.47ꢀ
AA?BB?, 2H, H2?, H6?), 7.16ꢀ7.11 (m AA?BB?, 2H,
H3?, H5?), 5.02 (s 2H, CH2). 13C NMR (DMSO-d6) d
163.4, 159.8 (d, Jꢃ229.8 Hz), 149.3, 147.2, 140.8, 132.0
(d, Jꢃ12.6 Hz), 130.2 (d, Jꢃ33.3 Hz), 129.0, 117.7,
117.2, 115.3 (d, Jꢃ85.2 Hz), 110.8, 45.1.
/
2.40 Hz, H5),
(KBr): n(CÄ
/
/
/7.41 (m
C16H12FNO4 (301.3) calc.: 63.79% C, 4.65% N, 4.01%
H; found: 63.45% C, 4.60% N, 4.07% H. 1H NMR
/
(DMSO-d6) d 7.52ꢀ
7.16ꢀ7.11 (m AA?BB?, 2H, H3?, H5?), 5.02 (s, 2H, CH2),
3.91 s, 3H, OCH3). 13C NMR (DMSO-d6) d 163.3, 160.5
(d, Jꢃ202.50 Hz), 147.9, 146.8, 142.3, 132.5 (d, Jꢃ
12.60 Hz), 130.2 (d, Jꢃ31.80 Hz), 125.5, 118.3, 117.9,
115.4, 115.2 (d, Jꢃ6.60 Hz), 56.6, 44.7.
/
7.32 (m 5H, H5, H6, H7, H2?, H6?),
/
/
/
/
/
/
/
/
/
3.1.40. 3-(4-Fluorobenzyl)-7-methoxy-2H-1,3-
benzoxazine-2,4(3H)-dione (4g)
White crystals. Yield 56%, m.p. 166ꢀ
/
168 8C. IR
3.1.44. 3-(4-Fluorobenzyl)-6-methoxy-2H-1,3-
benzoxazine-2,4(3H)-dione (4k)
(KBr): n(CÄ
/
O) 1692, 1751 cmꢁ1, log Pꢃ
/3.10. For
C16H12FNO4 (301.3) calc.: 63.79% C, 4.65% N, 4.01%
H; found: 63.89% C, 4.55% N, 4.24% H. 1H NMR
White crystals. Yield 47%, m.p. 160ꢀ
/
161 8C. IR
(KBr): n(CÄ
/
O) 1689, 1750 cmꢁ1, log Pꢃ
/
3.10. For
(DMSO-d6) d 7.88 (d, 1H, J(5,6)ꢃ
7.38 (m AA?BB?, 2H, H2?, H6?), 7.16ꢀ
2H, H3?, H5?), 7.01ꢀ6.99 (m, 2H, H6, H8), 5.01 (s, 2H,
CH2), 3.87 (s, 3H, OCH3). 13C NMR (DMSO-d6) d
165.8, 161.7, 160.2 (d, Jꢃ200.75 Hz), 154.5, 148.3,
132.7 (d, Jꢃ2.85 Hz), 130.2 (d, Jꢃ7.95 Hz), 129.0,
115.4 (d, Jꢃ21.08 Hz), 113.5, 107.1, 100.5, 56.6, 44.4.
/
9.00 Hz, H5), 7.41ꢀ
/
C16H12FNO4 (301.3) calc.: 63.79% C, 4.65% N, 4.01%
H; found: 63.86% C, 4.65% N, 4.13% H. 1H NMR
/
7.10 (m AA?BB?,
/
(DMSO-d6) d 7.46ꢀ
7.19ꢀ7.10 (m AA?BB?, 2H, H3?, H5?), 5.03 (s, 2H, CH2),
3.82 (s, 3H, OCH3). 13C NMR (DMSO-d6) d 163.3,
160.3 (d, Jꢃ169.80 Hz), 156.5, 148.1, 146.8, 132.6 (d,
Jꢃ12.3 Hz), 130.2 (d, Jꢃ32.10 Hz), 124.4, 118.1, 115.3
(d, Jꢃ85.50 Hz), 114.8, 108.9, 56.1, 44.7.
/
7.34 (m, 5H, H5, H6, H7, H2?, H6?),
/
/
/
/
/
/
/
/
/
3.1.41. 3-(4-Fluorobenzyl)-6-nitro-2H-1,3-benzoxazine-
2,4(3H)-dione (4h)
3.1.45. 3-(3,4-Dichlorobenzyl)-2H-1,3-benzoxazine-
2,4(3H)-dione (5a)
Yellow crystals. Yield 39%, m.p. 188ꢀ
/
191 8C. IR
(KBr): n(CÄ
/
O) 1701, 1771 cmꢁ1, log Pꢃ
/2.60. For
White crystals. Yield 51%, m.p. 154ꢀ
/
156 8C, Ref. [7]
C15H9FN2O5 (316.2) calc.: 56.97% C, 8.86% N, 2.87%
H; found: 57.18% C, 8.93% N, 2.55% H. 1H NMR
153ꢀ156 8C. IR: n(CÄ
/
/
O) 1687, 1761 cmꢁ1, log Pꢃ
/4.19.
For C15H9Cl2NO3 (322.1) calc.: 55.93% C, 4.35% N,
2.82% H; found: 55.86% C, 4.20% N, 2.84% H. 1H
(DMSO-d6) d 8.63 (dd, 1H, J(7,8)ꢃ
2.40 Hz, H7), 8.58 (d, 1H, J(5,7)ꢃ2.40 Hz, H5), 7.70 (d,
1H, J(7,8)ꢃ9.00 Hz, H8), 7.49ꢀ7.44 (m AA?BB?, 2H,
H2?, H6?), 7.18ꢀ7.12 (m AA?BB?, 2H, H3?, H5?), 5.05 (s,
2H, CH2). 13C NMR (DMSO-d6) d 163.4, 160.2, 158.1
(d, Jꢃ258.2 Hz), 147.4, 144.3, 132.0 (d, Jꢃ12.3 Hz),
/
9.00 Hz, J(5,7)ꢃ
/
/
NMR (DMSO-d6) d 7.98 (dd, 1H, J(5,6)ꢃ
J(5,7)ꢃ2.10 Hz, H5), 7.83ꢀ7.79 (m, 1H, H7), 7.68 (d,
1H, J(2?,6?)ꢃ2.10 Hz, H2?), 7.56 (d, 1H, J(5?,6?)ꢃ8.10
Hz, H5?), 7.47ꢀ7.36 (m, 3H, H6, H8, H6?), 5.03 (s, 2H,
CH2). 13C NMR (DMSO-d6) d 160.9, 152.7, 148.2,
/8.10 Hz,
/
/
/
/
/
/
/
/
/
/

1144
K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ1149
/
137.5, 136.5, 131.2, 130.6, 130.1, 129.9, 128.3, 127.5,
125.5, 116.6, 114.6, 44.4.
J(5?,6?)ꢃ
Hz, J(2?,6?)ꢃ
/
8.40 Hz, H5?), 7.36 (dd, 1H, J(5?,6?)ꢃ
/
8.40
/
1.80 Hz, H6?), 7.33 d, 1H, J(7,8)ꢃ
/
8.70
Hz, H8), 5.03 (s, 2H, CH2), 2.38 (s, 3H, CH3). 13C NMR
(DMSO-d6) d 160.8, 150.8, 148.3, 137.5, 137.3, 135.1,
131.2, 130.7, 130.1, 129.9, 128.3, 127.0, 116.4, 114.1,
44.4, 20.3.
3.1.46. 6-Bromo-3-(3,4-dichlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (5b)
White crystals. Yield 65%, m.p. 175ꢀ
/
177 8C. IR
(KBr): n(CÄ
/
O) 1701, 1770 cmꢁ1, log Pꢃ
/5.02. For
C15H8BrCl2NO3 (401.0) calc.: 44.92% C, 3.49% N,
2.01% H; found: 45.06% C, 3.16% N, 2.20% H. 1H
3.1.50. 6,8-Dibromo-3-(3,4-dichlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (5f)
NMR (DMSO-d6) d 8.05 (d, 1H, J(5,7)ꢃ
7.99 (dd, 1H, J(5,7)ꢃ8.70 Hz, J(7,8)ꢃ2.40 Hz, H7),
7.68 (d, 1H, J(2?,6?)ꢃ2.40 Hz, H2?), 7.58 (d, 1H,
J(5?,6?)ꢃ8.70 Hz, H5?), 7.43 (d, 1H, J(7,8)ꢃ8.70 Hz,
2.40 Hz,
/
2.70 Hz, H5),
White crystals. Yield 59%, m.p. 217ꢀ
/
219 8C. IR
/
/
(KBr): n(CÄ
/
O) 1699, 1769 cmꢁ1, log Pꢃ
/
5.85. For
/
C15H7Br2Cl2NO3 (479.9) calc.: 37.54% C, 2.92% N,
1.47% H; found: 37.71% C, 2.82% N, 1.60% H. 1H
/
/
H8), 7.38 (dd, 1H, J(5?,6?)ꢃ
/
8.70 Hz, J(2?,6?)ꢃ
/
NMR (DMSO-d6) d 8.38 (d, 1H, J(5,7)ꢃ
8.05 (d, 1H, J(5,7)ꢃ2.70 Hz, H7), 7.69 (d, 1H,
J(2?,6?)ꢃ1.80 Hz, H2?), 7.58 (d, 1H, J(5?,6?)ꢃ8.10
8.10 Hz, J(2?,6?)ꢃ
/2.70 Hz, H5),
H6?), 5.02 (s, 2H, CH2). 13C NMR (DMSO-d6) d 159.9,
151.9, 147.8, 138.9, 137.2, 131.2, 130.6, 130.2, 129.9,
129.4, 128.3, 119.1, 117.1, 116.6, 44.6.
/
/
/
Hz, H5?), 7.40 (dd, 1H, J(5?,6?)ꢃ
/
/
1.80 Hz, H6?), 5.03 (s, 2H, CH2). 13C NMR (DMSO-
d6) d 159.5, 149.3, 147.3, 140.8, 136.9, 131.1, 130.6,
130.2, 129.7, 129.0, 128.3, 117.8, 117.2, 110.7, 44.8.
3.1.47. 6-Chloro-3-(3,4-dichlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (5c)
White crystals. Yield 57%, m.p. 171ꢀ
/
173 8C. IR
(KBr): n(CÄ
/
O) 1695, 1757 cmꢁ1, log Pꢃ
/4.75. For
3.1.51. 3-(3,4-Dichlorobenzyl)-7-methoxy-2H-1,3-
benzoxazine-2,4(3H)-dione (5g)
C15H8Cl3NO3 (356.6) calc.: 50.52% C, 3.93% N, 2.26%
H; found: 50.45% C, 3.83% N, 2.18% H. 1H NMR
White crystals. Yield 53%, m.p. 132ꢀ
/
135 8C. IR
(DMSO-d6) d 7.94 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.40 Hz, H7), 7.69
(d, 1H, J(2?,6?)ꢃ2.10 Hz, H2?), 7.57 (d, 1H, J(5?,6?)ꢃ
8.10 Hz, H5?), 7.51 (d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.38
2.10 Hz, H6?),
/
2.70 Hz, H5), 7.88
(KBr): n(CÄ
/
O) 1693, 1755 cmꢁ1, log Pꢃ
/
4.06. For
/
/
C16H11Cl2NO4 (352.2) calc.: 54.57% C, 3.98% N,
3.15% H; found: 54.25% C, 3.86% N, 3.16% H. 1H
/
/
/
NMR (DMSO-d6) d 7.87 (dd, 1H, J(5,6)ꢃ
J(5,8)ꢃ0.60 Hz, H5), 7.66 (d, 1H, J(2?,6?)ꢃ
H2?), 7.56 (d, 1H, J(5?,6?)ꢃ8.40 Hz, H5?), 7.46 (dd, 1H,
J(5?,6?)ꢃ8.40 Hz, J(2?,6?)ꢃ1.80 Hz, H6?), 7.02ꢀ6.99
(m, 2H, H6, H8), 5.01 (s, 2H, CH2), 3.88 (s, 3H, OCH3).
13C NMR (DMSO-d6) d 165.8, 160.3, 154.6, 148.4,
137.6, 131.1, 130.7, 130.2, 129.9, 128.9, 128.3, 113.4,
107.3, 100.5, 56.6, 44.2.
/
8.40 Hz,
1.80 Hz,
(dd, 1H, J(5?,6?)ꢃ
/
8.10 Hz, J(2?,6?)ꢃ
/
/
/
5.03 (s, 2H, CH2). 13C NMR (DMSO-d6) d 160.0, 151.5,
147.9, 137.2, 136.1, 131.2, 130.6, 130.2, 129.9, 129.4,
128.4, 126.5, 118.9, 116.3, 44.6.
/
/
/
/
3.1.48. 6,8-Dichloro-3-(3,4-dichlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (5d)
White crystals. Yield 49%, m.p. 184ꢀ
/
186 8C. IR
(KBr): n(CÄ
/
O) 1699, 1772 cmꢁ1, log Pꢃ
/5.30. For
3.1.52. 3-(3,4-Dichlorobenzyl)-6-nitro-2H-1,3-
benzoxazine-2,4(3H)-dione (5h)
C15H7Cl4NO3 (391.0) calc.: 46.07% C, 3.58% N, 1.80%
H; found: 46.05% C, 3.47% N, 1.87% H. 1H NMR
Yellow crystals. Yield 46%, m.p. 170ꢀ
/
172 8C. IR
(DMSO-d6) d 8.20 (d, 1H, J(5,7)ꢃ
(d, 1H, J(5,7)ꢃ2.70 Hz, H7), 7.69 d, 1H, J(2?,6?)ꢃ
Hz, H2?), 7.58 (d, 1H, J(5?,6?)ꢃ8.10 Hz, H5?), 7.40 (dd,
2.10 Hz, H6?), 5.03 (s,
/
2.70 Hz, H5), 7.93
(KBr): n(CÄ
/
O) 1707, 1771 cmꢁ1, log Pꢃ
/
3.70. For
/
/
2.10
C15H8Cl2N2O5 (367.1) calc.: 49.07% C, 7.63% N,
2.20% H; found: 49.39% C, 7.51% N, 1.89% H. 1H
/
1H, J(5?,6?)ꢃ
/
8.10 Hz, J(2?,6?)ꢃ
/
NMR (DMSO-d6) d 8.64ꢀ
7.70 (m, 2H, H2?, H8), 7.59 (d, 1H, J(5?,6?)ꢃ
/
8.59 (m, 2H, H5, H7), 7.73ꢀ
8.40 Hz,
8.40 Hz, J(2?,6?)ꢃ2.40
/
2H, CH2). 13C NMR (DMSO-d6) d 159.5, 147.8, 147.1,
136.9, 135.4, 131.2, 130.6, 130.2, 129.7, 129.3, 128.4,
125.6, 121.5, 117.6, 44.8.
/
H5?), 7.43 (dd, 1H, J(5?,6?)ꢃ
/
/
Hz, H6?), 5.06 (s, 2H, CH2). 13C NMR (DMSO-d6) d
159.9, 156.4, 147.4, 144.3, 136.9, 131.1, 130.9, 130.6,
130.3, 129.9, 128.4, 123.0, 118.5, 115.7, 44.8.
3.1.49. 3-(3,4-Dichlorobenzyl)-6-methyl-2H-1,3-
benzoxazine-2,4(3H)-dione (5f)
White crystals. Yield 67%, m.p. 130ꢀ
/
132 8C. IR
3.1.53. 7-Chloro-3-(3,4-dichlorobenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (5i)
(KBr): n(CÄ
/
O) 1689, 1753 cmꢁ1, log Pꢃ
/4.68. For
C16H11Cl2NO3 (336.2) calc.: 57.17% C, 4.17% N,
3.30% H; found: 56.78% C, 4.31% N, 3.03% H. 1H
White crystals. Yield 57%, m.p. 172ꢀ
/
174 8C. IR
(KBr): n(CÄ
/
O) 1698, 1758 cmꢁ1, log Pꢃ
/
4.75. For
NMR (DMSO-d6) d 7.77 (d, 1H, J(5,7)ꢃ
7.67 (d, 1H, J(2?,6?)ꢃ1.80 Hz, H2?), 7.62 (dd, 1H,
J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ1.80 Hz, H7), 7.56 (d, 1H,
/
1.80 Hz, H5),
C15H8Cl3NO3 (356.6) calc.: 50.52% C, 3.93% N, 2.26%
H; found: 50.24% C, 3.83% N, 2.33% H. 1H NMR
/
/
/
(DMSO-d6) d 7.97 (d, 1H, J(5,6)ꢃ
/
8.40 Hz, H5), 7.71ꢀ
/

K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ
/1149
1145
4.97 (s, 2H, CH2), 3.70 (s, 3H, OCH3). 13C NMR
(DMSO-d6) d 159.7, 158.9, 151.8, 147.7, 138.9, 129.8,
129.4, 128.0, 119.2, 117.1, 116.4, 113.9, 55.2, 44.9.
?
7.68 (m, 2H, H2?, H8), 7.58 (d, 1H, J(5?,6?)ꢃ
H5?), 7.50 (dd, 1H, J(5,6)ꢃ8.40 Hz, J(6,8)ꢃ
8.40 Hz, J(2?,6?)ꢃ
/
8.40 Hz,
2.10 Hz,
2.10 Hz,
/
/
H6), 7.38 (dd, 1H, J(5?,6?)ꢃ
/
/
H6?), 5.02 (s, 2H, CH2). 13C NMR (DMSO-d6) d 160.3,
153.2, 147.9, 140.5, 137.3, 131.2, 130.6, 130.2, 129.9,
129.1, 128.3, 125.8, 116.8, 113.8, 44.5
3.1.58. 6-Chloro-3-(4-methoxybenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (6c)
White crystals. Yield 55%, m.p. 155ꢀ
/
161 8C. IR
O) 1696, 1769 cmꢁ1, log Pꢃ
/
3.50. For
3.1.54. 3-(3,4-Dichlorobenzyl)-8-methoxy-2H-1,3-
benzoxazine-2,4(3H)-dione (5j)
(KBr): n(CÄ
/
C16H12ClNO4 (317.7) calc.: 60.48% C, 4.41% N, 3.81%
H; found: 60.26% C, 4.31% N, 3.74% H. 1H NMR
White crystals. Yield 56%, m.p. 149ꢀ
/
151 8C. IR
(KBr): n(CÄ
/
O) 1696, 1758 cmꢁ1, log Pꢃ
/4.06. For
(DMSO-d6) d 7.93 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ9.00 Hz, J(5,7)ꢃ2.70 Hz, H7), 7.49
(d, 1H, J(7,8)ꢃ9.00 Hz, H8), 7.33ꢀ7.30 (m AA?BB?,
2H, H2?, H6?), 6.88ꢀ
/
2.70 Hz, H5), 7.85
C16H11Cl2NO4 (352.2) calc.: 54.57% C, 3.98% N,
3.15% H; found: 54.80% C, 3.90% N, 3.18% H. 1H
/
/
/
/
NMR (DMSO-d6) d 7.67 (d, 1H, J(2?,6?)ꢃ
/
1.80 Hz,
7.46
/
6.85 (m AA?BB?, 2H, H3?, H5?),
4.97 (s, 2H, CH2), 3.71 (s, 3H, OCH3). 13C NMR
(DMSO-d6) d 159.8, 158.9, 151.3, 147.7, 136.1, 129.8,
129.5, 128.1, 126.5, 118.9, 116.0, 113.9, 55.3, 45.0.
H2?), 7.56 (d, 1H, J(5?,6?)ꢃ8.10 Hz, H5?), 7.49ꢀ
/
/
?
(m, 2H, H5, H7), 7.41ꢀ7.35 (m, 2H, H6, H6?), 5.04 (s,
/
2H, CH2), 3.82 (s, 3H, OCH3). 13C NMR (DMSO-d6) d
160.8, 156.5, 148.2, 146.9, 138.8, 133.2, 130.4, 127.7,
127.6, 126.5, 124.3, 118.1, 114.8, 108.8, 56.1, 44.9.
3.1.59. 6,8-Dichloro-3-(4-methoxybenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (6d)
3.1.55. 3-(3-Chlorobenzyl)-6-methoxy-2H-1,3-
benzoxazine-2,4(3H)-dione (5k)
White crystals. Yield 58%, m.p. 155ꢀ
/
157 8C. IR
(KBr): n(CÄ
/
O) 1707, 1772 cmꢁ1, log Pꢃ
/
4.06. For
White crystals. Yield 66%, m.p. 139ꢀ
/
140 8C. IR
C16H11Cl2NO4 (352.2) calc.: 54.57% C, 3.98% N,
3.15% H; found: 54.87% C, 3.90% N, 3.07% H. 1H
(KBr): n(CÄ
/
O) 1693, 1752 cmꢁ1, log Pꢃ
/3.50. For
C16H12ClNO4 (317.7) calc.: 60.48% C, 4.41% N, 3.81%
H; found: 60.35% C, 4.36% N, 3.95% H. 1H NMR
NMR (DMSO-d6) d 8.18 (d, 1H, J(5,7)ꢃ/2.40 Hz, H5),
7.91 (d, 1H, J(5,7)ꢃ2.40 Hz, H7), 7.33ꢀ
/
/7.30 (m
(DMSO-d6) d 7.45 (bs, 1H, H5), 7.40ꢀ7.37 (m, 3H, H7,
/
AA?BB?, 2H, H2?, H6?), 6.88ꢀ
/
6.85 (m AA?BB?, 2H,
H2?, H4?), 7.34ꢀ7.31 (m, 3H, H8, H5?, H6?), 5.04 (s, 2H,
/
H3?, H5?), 4.97 (s, 2H, CH2), 3.71 (s, 3H, OCH3). 13C
NMR (DMSO-d6) d 159.4, 158.9, 147.7, 147.0, 135.4,
129.8, 129.3, 127.7, 127.6, 121.6, 117.4, 113.9, 55.3, 45.2.
?
CH2), 3.83 (s, 3H, OCH3). 13C NMR (DMSO-d6) d
160.8, 156.4, 148.2, 146.9, 138.9, 133.3, 130.5, 127.7,
127.6, 126.6, 124.3, 118.2, 114.9, 108.8, 56.2, 45.0.
3.1.60. 3-(4-Methoxybenzyl)-6-methyl-2H-1,3-
benzoxazine-2,4(3H)-dione (6e)
3.1.56. 3-(4-Methoxybenzyl)-2H-1,3-benzoxazine-
2,4(3H)-dione (6a)
White crystals. Yield 64%, m.p. 135ꢀ
/
137 8C. IR
White crystals. Yield 49%, m.p. 110ꢀ
104ꢀ106 8C. IR (KBr): n(CÄ
O) 1698, 1753 cmꢁ1
log Pꢃ2.95. For C16H13NO4 (283.3) calc.: 67.84% C,
4.94% N, 4.63% H; found: 67.55% C, 4.77% N, 4.69%
/
112 8C, Ref. [7]
(KBr): n(CÄ
/
O) 1693, 1757 cmꢁ1, log Pꢃ
/
3.43. For
/
/
,
C17H15NO4 (297.3) calc.: 68.68% C, 4.71% N, 5.09%
H; found: 68.61% C, 4.68% N, 5.04% H. 1H NMR
/
1
(DMSO-d6) d 7.77 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.10 Hz, J(5,7)ꢃ1.80 Hz, H7), 7.32
(d, 1H, J(7,8)ꢃ8.10 Hz, H8), 7.30ꢀ7.28 (m AA?BB?,
2H, H2?, H6?), 6.88ꢀ
/
1.80 Hz, H5), 7.60
H. H NMR (DMSO-d6) d 7.99 (dd, 1H, J(5,6)ꢃ
Hz, J(5,7)ꢃ1.80 Hz, H5), 7.85ꢀ7.78 (m, 1H, H7), 7.45ꢀ
7.40 (m, 2H, H6, H8), 7.32ꢀ7.29 (m AA?BB?, 2H H2?,
/
8.40
/
/
/
/
/
/
/
/
/
6.85 (m AA?BB?, 2H, H3?, H5?),
H6?), 6.88ꢀ
/
6.85 (m AA?BB?, 2H, H3?, H5?), 4.98 (s, 2H,
4.97 (s, 2H, CH2), 3.70 (s, 3H, OCH3). 13C NMR
(DMSO-d6) d 160.7, 158.9, 150.6, 148.1, 137.3, 135.1,
129.7, 128.4, 127.0, 116.4, 114.0, 55.3, 44.7, 20.3.
?
CH2), 3.70 (s, 3H, OCH3). 13C NMR (DMSO-d6) d
160.7, 158.9, 152.5, 148.1, 136.6, 129.7, 128.3, 127.6,
125.6, 116.6, 114.4, 113.9, 55.3, 44.8.
?
3.1.57. 6-Bromo-3-(4-methoxybenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (6b)
3.1.61. 6,8-Dibromo-3-(4-methoxybenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (6f)
White crystals. Yield 56%, m.p. 163ꢀ
/
169 8C. IR
White crystals. Yield 68%, m.p. 168ꢀ
/
170 8C. IR
(KBr): n(CÄ
/
O) 1693, 1768 cmꢁ1, log Pꢃ
/3.77. For
(KBr): n(CÄ
/
O) 1701, 1772 cmꢁ1, log Pꢃ
/
4.60. For
C16H12BrNO4 (362.2) calc.: 53.06% C, 3.87% N, 3.34%
H; found: 53.44% C, 3.50% N, 3.63% H. 1H NMR
C16H11Br2NO4 (441.1) calc.: 43.57% C, 3.18% N,
2.51% H; found: 43.62% C, 3.01% N, 2.52% H. 1H
(DMSO-d6) d 8.06 (d, 1H, J(5,7)ꢃ
(dd, 1H, J(7,8)ꢃ8.70 Hz, J(5,7)ꢃ2.70 Hz, H7), 7.42
(d, 1H, J(7,8)ꢃ8.70 Hz, H8), 7.32ꢀ7.29 (m AA?BB?,
2H, H2?, H6?), 6.88ꢀ6.85 (m AA?BB?, 2H, H3?, H5?),
/
2.40 Hz, H5), 7.96
NMR (DMSO-d6) d 8.36 (d, 1H, J(5,7)ꢃ
8.04 (d, 1H, J(5,7)ꢃ2.40 Hz, H7), 7.33ꢀ
AA?BB?, 2H, H2?, H6?), 6.88ꢀ
/
2.40 Hz, H5),
/
/
/
/7.30 (m
/
/
/
6.85 (m AA?BB?, 2H,
?
/
H3?, H5?), 4.96 (s, 2H, CH2), 3.71 (s, 3H, OCH3). 13C

1146
K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ1149
/
NMR (DMSO-d6) d 159.3, 158.9, 149.2, 147.1, 140.8,
129.8, 129.0, 127.8, 117.6, 117.2, 113.9, 110.8, 55.3, 45.2.
3.2. Microbiology
The following strains, obtained from the Czech
National Collection of Type Cultures (CNCTC), Na-
tional Institute of Public Health, Prague, were used for
the evaluation of in vitro antimycobacterial activity: M.
kansasii CNCTC My 235/80, and M. avium CNCTC
My 330/88, and a clinical isolate of Mycobacterium
kansasii 6 509/ 96. Antimycobacterial activity of the
compounds against these strains was determined in the
3.1.62. 3-(4-Methoxybenzyl)-6-nitro-2H-1,3-
benzoxazine-2,4(3H)-dione (6h)
Yellow crystals. Yield 56%, m.p. 143ꢀ
/
151 8C. IR
(KBr): n(CÄ
/
O) 1704, 1771 cmꢁ1, log Pꢃ
/
2.59. For
C16H12N2O6 (328.3) calc.: 58.54% C, 8.53% N, 3.68%
H; found: 58.63% C, 8.36% N, 3.69% H. 1H NMR
(DMSO-d6) d 8.63ꢀ
J(7,8)ꢃ9.00 Hz, H8), 7.35ꢀ
H6?), 6.88ꢀ
/
8.57 (m, 2H, H5, H7), 8.69 (d, 1H,
ˇ
ˇ
Sula semisynthetic medium (SEVAC, Prague). The Sula
liquid medium (with bovine serum) is routinely used in
the Czech Republic. Each strain was simultaneously
/
/
7.32 (m AA?BB?, 2H, H2?,
/
6.86 (m AA?BB?, 2H, H3?, H5?), 4.99 (s, 2H,
CH2), 3.70 (s, 3H, OCH3). 13C NMR (DMSO-d6) d
159.7, 158.9, 156.3, 147.3, 144.3, 130.9, 129.9, 127.8,
123.1, 118.6, 115.4, 113.9, 55.3, 45.2.
?
inoculated into a Petri dish containing the Lowensteinꢀ
/
¨
Jensen medium for the control of the sterility of the
inoculum and its growth. The compounds were added to
the medium in DMSO solutions. The final concentra-
tions were 1000, 500, 250, 125, 62.5, 32, 16, 8, 4, 2, 1
mmol/l. The minimum inhibitory concentrations were
determined after incubation at 37 8C for 21 days (see
Table 1). MIC was the lowest concentration of an
antimycobacterially effective substance (on the above-
stated concentration scale), at which inhibition of the
growth of the mycobacteria occurred.
3.1.63. 7-Chloro-3-(4-methoxybenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (6i)
White crystals. Yield 64%, m.p. 153ꢀ
/
156 8C. IR
(KBr): n(CÄ
/
O) 1690, 1768 cmꢁ1, log Pꢃ
/3.50. For
C16H12ClNO4 (317.7) calc.: 60.48% C, 4.41% N, 3.81%
H; found: 60.87% C, 4.15% N, 3.92% H. 1H NMR
(DMSO-d6) d 7.98 (d, 1H, J(5,6)ꢃ
(d, 1H, J(6,8)ꢃ1.80 Hz, H8), 7.50 (dd, 1H, J(5,6)ꢃ
8.10 Hz, J(6,8)ꢃ1.80 Hz, H6), 7.32ꢀ7.29 (m AA?BB?,
2H, H2?, H6?), 6.88ꢀ
/8.10 Hz, H5), 7.68
/
/
/
/
/
6.85 (m AA?BB?, 2H, H3?, H5?),
3.3. Calculations
4.96 (s, 2H, CH2), 3.70 (s, 3H, OCH3). 13C NMR
(DMSO-d6) d 160.0, 158.9, 153.0, 147.8, 140.5, 129.7,
129.2, 128.1, 125.9, 116.8, 113.9, 113.6, 55.3, 44.9.
?
Logarithms of the partition coefficients were calcu-
lated using ChemOffice 6 software (Table 2). All
regression equations were set up using the Linreg and
Multireg H programmes (Klemera) for Microsoft Excel.
The values of the Hammett constants (Table 3) were
taken from Ref. [8].
3.1.64. 8-Methoxy-3-(4-methoxybenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (6j)
White crystals. Yield 45%, m.p. 165ꢀ
/
167 8C. IR
(KBr): n(CÄ
/
O) 1684, 1756 cmꢁ1, log Pꢃ
/2.82. For
C17H15NO5 (313.3) calc.: 65.17% C, 4.47% N, 4.83%
H; found: 64.82% C, 4.33% N, 4.94% H. 1H NMR
(CDCl3) d 7.49ꢀ
/
7.46 (m, 2H, H5, H7), 7.37ꢀ
/
7.28 (m,
4. Results and discussion
3H, H6, H2?, H6?), 6.88ꢀ
/
6.85 (m AA?BB?, 2H, H3?,
H5?), 4.97 (s, 2H, CH2), 3.90 (s, 3H, OCH3), 3.70 (s, 3H,
To set up the regression equations, we employed the
‘‘Linreg’’ programme developed by Klemera for Micro-
soft Excel. The values of antimycobacterial activity of
N-benzylsalicylamides were taken from the literature [5].
The antimycobacterial activities of N-benzylsalicyla-
OCH3). 13C NMR (CDCl3) d 160.7, 158.9, 147.8, 146.8,
?
142.2, 129.7, 128.3, 125.5, 118.7, 117.9, 11.1, 113.9, 56.6,
55.3, 44.8.
mines correlate (see Eqs. (1)ꢀ(6)) with those of 3-
/
3.1.65. 6-Methoxy-3-(4-methoxybenzyl)-2H-1,3-
benzoxazine-2,4(3H)-dione (6k)
benzyl-2H-1,3-benzoxazin-2,4(3H)-diones. Thus, it ap-
pears that the mechanisms of antimycobacterial activity
are identical. Recently, we have found similar correla-
tions for salicylanilides and 3-aryl-2H-1,3-benzoxazin-
2,4(3H)-diones [4].
White crystals. Yield 63%, m.p. 158ꢀ
/
159 8C. IR
(KBr): n(CÄ
/
O) 1685, 1751 cmꢁ1, log Pꢃ
/2.82. For
C17H15NO5 (313.3) calc.: 65.17% C, 4.47% N, 4.83%
H; found: 65.22% C, 4.11% N, 4.80% H. 1H NMR
(CDCl3) d 7.40ꢀ
/
7.36 (m, 3H, H5, H7, H8), 7.31ꢀ
/
7.29
(m AA?BB?, 2H, H2?, H6?), 6.88ꢀ
/
6.84 (m AA?BB?, 2H,
4.1. M. avium My 330/88
H3?, H5?), 4.98 (s, 2H, CH2), 3.83 (s, 3H, OCH3), 3.70 (s,
3H, OCH3). 13C NMR (CDCl3) d 160.6, 158.9, 156.5,
?
log MICBO ꢃ0:949(90:111) log MICSA ꢂ0:131(90:219)
rꢃ0.90 sꢃ0.20 nꢃ19 Fꢃ73
(1)
148.1, 146.8, 129.7, 128.3, 124.4, 118.1, 114.7, 113.9,
108.8, 56.1, 55.3, 44.8.
/
/
/
/

K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ
/1149
1147
Table 1
In vitro antimycobacterial activity of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones
Comp.
Minimum inhibitory concentrations (MICs) mmol lꢁ1
Incubation 21 days
R1
R2
M. avium My 330/88
M. kansasii My 235/80
M. kansasii 6509/96
1a
1b
1c
1d
1e
1f
H
6-Br
H
62.5
62.5
62.5
250
62.5
125
62.5
125
125
H
6-Cl
H
62.5
250
62.5
6,8-Cl2
6-CH3
6,8-Br2
7-CH3O
6-NO2
7-Cl
H
125
125
H
62.5
a
a
a
H
a
a
a
a
1g
1h
1i
H
H
250
a
250
a
H
62.5
a
a
a
a
a
a
a
a
a
a
a
a
1k
1l
8-CH3O
6-CH3O
H
H
a
H
4-Cl
2a
2b
2c
2d
2e
2f
32
a
125
a
6-Br
6-Cl
4-Cl
4-Cl
a
a
a
a
a
32
a
6,8-Cl2
6-CH3
6,8-Br2
7-CH3O
6-NO2
7-Cl
4-Cl
4-Cl
a
a
a
a
a
a
a
4-Cl
4-Cl
2g
2h
2i
4-Cl
4-Cl
250
a
125
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
2k
2l
8-CH3O
6-CH3O
H
4-Cl
4-Cl
3a
3b
3c
3d
3e
3f
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-F
62.5
a
6-Br
6-Cl
a
a
a
a
a
6,8-Cl2
6-CH3
6,8-Br2
7-CH3O
6-NO2
7-Cl
3g
3h
3i
500
a
500
a
250
a
a
a
a
a
a
a
3k
3l
8-CH3O
6-CH3O
H
4a
4b
4c
4d
4e
4f
125
250
a
250
a
6-Br
6-Cl
4-F
4-F
62.5
32
62.5
a
125
a
a
6,8-Cl2
6-CH3
6,8-Br2
7-CH3O
6-NO2
7-Cl
4-F
4-F
a
a
a
a
a
a
a
a
a
a
a
a
4-F
4-F
4g
4h
4i
4-F
4-F
62.5
a
125
a
125
a
4k
4l
8-CH3O
6-CH3O
H
4-F
4-F
a
a
a
5a
5b
5c
5d
5e
5f
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3-Cl
32
32
32
62.5
62.5
62.5
62.5
62.5
62.5
6-Br
6-Cl
6,8-Cl2
6-CH3
6,8-Br2
7-CH3O
6-NO2
7-Cl
125
a
125
a
125
a
a
a
a
a
a
a
5g
5h
5i
250
a
125
a
125
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
5k
5l
8-CH3O
6-CH3O
H
6a
6b
6c
6d
4-CH3O
4-CH3O
4-CH3O
4-CH3O
250
a
6-Br
6-Cl
a
a
6,8-Cl2

1148
K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ1149
/
Table 1 (Continued)
Comp.
Minimum inhibitory concentrations (MICs) mmol lꢁ1
Incubation 21 days
R1
R2
M. avium My 330/88
M. kansasii My 235/80
M. kansasii 6509/96
a
a
a
a
a
a
6e
6f
6-CH3
6,8-Br2
6-NO2
7-Cl
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
6h
6i
1000
125
500
a
250
a
a
a
a
a
a
6k
6l
8-CH3O
6-CH3O
a
INH
250
250
4
a
log MIC could not be determined due to a low solubility.
4.3. M. kansasii 6509/96
Table 2
Lipophilicity (log P) of compounds 1a-6l
log MICBO ꢃ0:524(90:100) log MICSA ꢂ1:062(90:210)
rꢃ0.83 sꢃ0.13 nꢃ14 Fꢃ27
(3)
Comp.
log P
Comp.
log P
Comp.
log P
/
/
/
/
1a
1b
1c
1d
1e
1f
3.07
3.90
3.63
4.19
3.56
4.73
2.95
2.46
3.63
2.95
2.95
3.63
4.46
4.19
4.75
4.12
5.29
3.50
3.08
4.19
3.50
3.50
3a
3b
3c
3d
3e
3f
3.56
4.39
4.12
4.68
4.05
5.22
3.43
2.88
4.12
3.43
3.43
3.23
4.06
3.79
4.35
3.72
4.89
3.10
2.60
3.79
3.10
3.10
5a
5b
5c
5d
5e
5f
4.19
5.02
4.75
5.30
4.68
5.85
4.06
3.70
4.75
4.06
3.50
2.95
3.77
3.50
4.06
3.43
4.60
2.59
3.50
2.82
2.82
The QSAR study of the antimycobacterial activity of
3-benzyl-2H-1,3-benzoxazine-2,4(3H)-diones includes
the results obtained after 21 days of incubation. The
structureꢀactivity relationships of the activity against
/
1g
1h
1i
3g
3h
3i
5g
5h
5i
M. avium were expressed by the classical Hansch
equations (optimum of log P is 5.13). Indicator para-
meter I was used for disubstituted benzoxazines (3-
benzyl-6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-dio-
nes).The influence of the electronic effects of the
substituents on the benzoxazine moiety was expressed
by the Hammett constants, with regard to their orienta-
tion to the hydroxy group in position 1 (s)O and to the
carbonyl group in position 4 (s)CO. The influence of the
substituents on the benzyl ring was not important.
According to equations 5 and 6, we did not obtain the
optimum of log P for the activity against both strains of
M. kansasii. More lipophilic compounds have probably
more favourable log P for antimycobacterial activity
against this species. The compounds under study are
more active than INH against standard strains of M.
avium and M. kansasii.
1k
1l
3k
3l
5k
5l
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
6a
6b
6c
6d
6e
6f
2g
2h
2i
4g
4h
4i
6h
6i
6k
6l
2k
2l
4k
4l
Table 3
Values of substituent constants
log MICM:avium21d ꢃꢁ1:878(90:510) log Pꢂ0:183(90:065)(log P)2
Substituent
sm
sp
H
Br
0
0
ꢂ0:670(90:141)(s)O ꢂ0:718(90:140)Iꢂ6:117(91:000)
(4)
0.39
0.37
0.71
0.07
0.12
0.34
0.23
0.23
0.78
0.17
0.27
0.06
Cl
rꢃ/0.94
sꢃ
/
0.16
nꢃ/22
Fꢃ32
/
NO2
CH3
OCH3
F
ꢁ/
ꢁ
ꢁ/
/
log MICM:kansasii21d
ꢃꢁ0:232(90:076)log Pꢂ0:489(90:168)(s)O
ꢂ0:481(90:166)I ꢂ2:756(90:308)
(5)
The values of the substituent constants were taken from Ref. [6]
rꢃ/0.85
sꢃ
/
0.19
nꢃ/17
Fꢃ11
/
4.2. M. kansasii My 235/80
log MICM:kansasiiklin:21d
ꢃꢁ0:183(90:047)log Pꢂ0:181(90:047)(s)CO ꢂ2:714(90:182)
(6)
log MICBO ꢃ0:848(90:200) log MICSA ꢂ0:487(90:414)
rꢃ0.80 sꢃ0.20 nꢃ12 Fꢃ18
(2)
/
/
/
/
rꢃ
/
0.71
sꢃ
/
0.16
nꢃ/19
Fꢃ9
/

K. Waisser et al. / Il Farmaco 58 (2003) 1137ꢀ
/1149
1149
[3] K. Waisser, M. Perˇina, P. Holy´, M. Pour, O. Buresˇ, J. Kunesˇ, V.
Klimesˇova´, Vl. Buchta, P. Kubanova´, J. Kaustova´, Antimycobac-
terial and antifungal isosters of salicylamides, Arch. Pharm. 336
Acknowledgements
This work is part of the research projects No. MSM
111600001 of the Ministry of Education Czech Republic
and was supported by grant 203/02/0082 Grant Agency
of Czech Republic,
(2003) 322ꢀ335.
/
[4] K. Waisser, K. Drazˇkova´, P. Holy´, K. Pala´t, Jr., J. Kaustova´,
Correlation of antimycobacterial activity of substituted salicylani-
lides and 3-aryl-2H-1,3-benzoxazine-2,4(3H)-diones. Folia Pharm.
Univ. Carol. 29 (2003) in press.
[5] K. Waisser, M. Perˇina, V. Klimesˇova´, J. Kaustova´, On the
relationship between the structure and antimycobacterial activity
substituted N-benzylsalicylamides, Collect. Czech. Chem. Com-
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